Bad news today from the fight against AIDS: the Merck STEP trial has been discontinued due to evidence that the vaccine neither prevents nor attenuates HIV infection. This is a serious setback, as the trial was utilizing a new strategy and had sufficiently promising results two years ago that it was actually expanded. While this doesn’t mark the death-knell of the CTL approach by any means, it is certainly a major disappointment and will probably send a number of approaches in development back to the drawing board.

The classic approaches to vaccination in humans have failed for HIV for a variety of reasons. Part of the difficulty is that HIV has such a high degree of variation. There’s no guarantee that any single vaccine could protect against every strain for any length of time. Moreover, vaccination using the virus itself is incredibly risky — even a virus that is missing the essential Nef protein from its RNA can damage the immune system. Experiments in SIV show that a damaged or attenuated virus only confers protection if it reproduces at low levels in the host, but at the same time this gives it a greater opportunity to revert to pathogenic status. For this reason, chemical inactivation, which truly kills the virus, doesn’t produce a viable vaccine because the virus does not stimulate sufficient antibodies to protect the patient.

The Merck vaccine used a different approach entirely, based on the idea of activating cytotoxic T lymphocytes. Rather than using inactivated HIV, the Merck team transplanted three HIV genes into an adenovirus (one of the viruses that produces the common cold). The idea was that these genes would get expressed into protein and displayed on the cell surface in the major histocompatibility complex. This would train T cells to attack any cell that the HIV virus had infected. Thus, the approach would not be to immobilize the virus with anitbodies, but rather to destroy any infected hosts cells before virus production really swung into gear. Even if it failed to prevent infection per se, it was hoped that this approach would arrest the development of an HIV infection into AIDS.

Unfortunately, this clever tack seems to have failed, at least in this application. It may take some time to understand why things did not work out, and maybe there was just an unfortunate choice of which HIV proteins were used or some other idiosyncratic issue with Merck’s particular formulation of the approach. Until a detailed post-mortem is complete, however, CTL-stimulation approaches will have to be evaluated in a harsher light, with a little less hope.